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J. Biol. Chem., Vol. 279, Issue 6, 4075-4083, February 6, 2004

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Cellular Carbonyl Stress Enhances the Expression of Plasminogen Activator Inhibitor-1 in Rat White Adipocytes via Reactive Oxygen Species-dependent Pathway^*

Yoko Uchida, Ken-ichi Ohba¶, Toshimasa Yoshioka||, Kaoru Irie, Takamura Muraki, and Yoshiro Maru

From the Departments of Pharmacology and ^||Medical Education, Tokyo Women's Medical University, School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan and the ^¶Department of Work Stress Control, National Institute of Industrial Health, 6-21-1 Nagao, Tama-Ku, Kawasaki City 214-8585, Japan

Carbonyl stress is one of the important mechanisms of tissue damage in vascular complications of diabetes. In the present study, we observed that the plasminogen activator inhibitor-1 (PAI-1) levels in serum and its gene expression in adipose tissue were up-regulated in aged OLETF rats, model animals of obese type 2 diabetes. To study the mechanism of PAI-1 up-regulation, we examined the effect of advanced glycation end products (AGEs) and the product of lipid peroxidation (4-hydroxy-2-nonenal (HNE)), both of which are endogenously generated under carbonyl stress. Stimulation of primary white adipocytes by either AGE or HNE resulted in the elevation of PAI-1 in culture medium and at mRNA levels. The up-regulation of PAI-1 was also observed by incubating the cells in high glucose medium (30 mM, 48 h). The stimulatory effects by AGE or high glucose were inhibited by antioxidant, pyrrolidine dithiocarbamate, and reactive oxygen scavenger, probucol, suggesting a pivotal role of oxidative stress in white adipocytes. We also found that the effect by HNE was inhibited by antioxidant, N-acetylcysteine and that a specific inhibitor of glutathione biosynthesis, L-buthionine-S,R-sulfoximine, augmented the effect of subthreshold effect of HNE. Bioimaging of reactive oxygen species (ROS) by a fluorescent indicator, 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate, revealed ROS production in white adipocytes treated with AGE or HNE. These results suggest that cellular carbonyl stress induced by AGEs or HNE may stimulate PAI-1 synthesis in and release from adipose tissues through ROS formation.

Received for publication, April 22, 2003 , and in revised form, November 5, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 81-3-3353-8111 (ext. 22513); Fax: 81-3-5269-7417; E-mail: uchiy{at}research.twmu.ac.jp.

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